Background
One of the most important problems in the pharmaceutical industry has been the preparation of dosage forms with improved visual characteristics. The shape, size and colour are all visual characteristics used to differentiate products, and the colouration of solid dosage forms is widespread, depending upon the physical properties of the product, the characteristics of the active ingredient and the geographic region in which the product is to be marketed.
There are a number of reasons to colour solid dosage forms, including:
•Identification. To help pharmacists and patients on multi-dosage regimes. A patient will often refer to the colour and shape of dosage form (e.g. 'the little blue tablet for my heartburn1) rather than the generic nomenclature and dosage level of the tablet;
•Flavour perception. The patient's expectation of the flavour and colour of a product is important; for example, consumers expect a cherry flavoured lozenge to be red;
•Brand identification. Colour offers the pharmaceutical manufacturer an easy route to brand identification in a highly competitive market;
•Quality perception. Colour can be added to increase the aesthetic value of the product, thereby increasing the perception of quality;
•Counterfeit prevention. The development of unique colours for a particular active drug and the application of coloured printing can help to reduce the risk of counterfeiting.
While both natural and synthetic colors are widely used, drug-makers are turning increasingly to natural colors as they develop new products with increased purity which is a very big concern.
A number of factors influence the decision to use natural colors. Synthetic colors remain popular, especially the commonly used FD&C colors Red #40, Yellow #5, Yellow #6 and Blue #1. However, synthetic colors pose some challenges. They are more difficult to produce and use, and each batch must be certified by the Food and Drug Administration. Synthetic colors may be used in amounts consistent with good manufacturing practices, but cannot be used in foods and beverages for which there is

an established standard of identity (unless added color is specifically authorized by the standard).
With the Food and Drug Administration re-examining its listed and approved FD&C and D&C lakes and withdrawing approval, considering withdrawing approval or introducing restrictions and new regulation for such lakes, there has been a demand in the food, drug and cosmetic industries for pigments that simulate closely and may be substituted for any lakes that the Food and Drug Administration may de-list or restrict.
Natural colors, typically manufactured from fruits and vegetables without added chemicals, don't have as strong a regulatory impact. The FDA does not actually recognize the term "natural color"; instead, what the pharmaceutical industry considers natural colors are "exempt from certification" in FDA terms.
These natural dye pigments simulate and are substitutes for FD&C and D&C lakes that are used for coloring food, drugs and cosmetics. Such lakes, and the color coating of pharmcaeuticals, confectionery, and food, are discussed in Colorcon Incorporated U.S. Pat. Nos. 3,909,284 issued Sept. 30, 1975, and US Pat. No. 3,576,663 issued Apr. 27, 1971, and the references cited therein, all of which are incorporated herein by reference.
The use of natural colors is also a powerful selling tool in today's marketplace. Because there's a high demand for natural products, the advantage is that you can use as a marketing tool the fact that the product is all natural, no synthetic colors added.
But natural colors have inherent challenges, as well. First natural colors are more expensive to use than synthetic colors. Secondly, compared with certified dyes, some of the natural colorants are less useful because they are not as temperature and light stable as desired.
The relative stability of selected dyes and pigments is very important when formulating with colorants (stability refers to the relative length of time a colorant remains chemically and physically unchanged). Factors that affect colour stability include light, oxidising and reducing agents, heat, pH, microbial contamination and solubility limits.
Colour bleeding is another factor that could make a mess or otherwise cause problems, especially in places with hot and humid climate. A very undesirable effect of bleeding is

the discolouration of pharmaceutical dosage forms. Prevention of colour bleeding is important not only because it improves product aesthetics, but because it lessens the apprehension of patients who have difficulty swallowing solid dosage forms.
Processes such as emulsification and microencapsulation are now used more frequently to improve the stability of natural colors. However these processes require an additional manufacturing step that adds to the manufacturing costs of the tablet.
With the foregoing and other coating compositions, the industry continues to desire a product which provides enhanced stability for the colorants. The industry has recognized the need for an improved technique, which is simple and economical, which would provide better relative stability of dyes and pigments than conventionally accepted methods. The process of preparing such an improved dosage form with enhanced technique economically and efficiently continues to be of interest.
Summary
In one general aspect there is provided a solid dosage form comprising:
a) a core comprising one or more therapeutically active agents,
b) an inner coat surrounding said core, comprising at least one water soluble
polymer and at least one natural pigment,
c) an outer coat surrounding the inner coat comprising at least one water
soluble polymer,
wherein the outer coat constitutes from about 0.5% to about 1.5% of the total weight of the dosage form.
This outer coating layer of water soluble polymer aids in preventing bleeding of the colour from underneath and also imparts a gloss to the solid dosage form, apart from providing an effective moisture barrier. Solid dosage forms provided herein have one or more enhanced properties such as higher gloss, better mouthfeel, non-tackiness, being swallowable with little or no accompanying liquid and better taste.
It is one of the aspects to provide a process for coating a solid dosage form comprising the steps of:
a) preparing an aqueous solution of at least one water soluble polymer and at least one natural pigment,

b) coating the aqueous solution of step (a) over the active core of the solid dosage
form to provide the inner coat, and
c) coating the inner coat of step (b) with at least one water soluble polymer to form
an outer coat,
wherein the outer coat constitutes from about 0.5% to about 1.5% of the total weight of the dosage form.
In another embodiment logos and brand names can be punched onto the core of the solid dosage form, and these intagliations would be clearly visible even after applying the outer coat.
In another embodiment the coatings have been applied to solid dosage forms which have been debossed with letters or a logo without bridging which would hide, or even obliterate, the debossed design.
Description
In carrying out the method of the invention, a solid dosage form is provided comprising a core of a therapeutically active agent, an inner coat of a water soluble polymer and a natural pigment and an outer coat of a water soluble polymer.
The coatings may be applied to solid dosage forms having wide variety of active ingredients. For example, it has been reported that multivitamin tablets are difficult to coat because of the lipophilic surface properties of the vitamins. Tablets comprising other difficult-to-coat active ingredients may also be readily coated with the coating compositions of this invention, providing elegant tablets.
Optionally, if desired, the core of the solid dosage form according to the present invention may further comprise various pharmaceutically acceptable excipients. The term 'pharmaceutically acceptable excipient' as used herein includes all physiologically acceptable excipients used in the pharmaceutical art of dispensing.
Examples include binders, diluents, lubricants, glidants, sweetening agents and flavoring agents.

Suitable binders include one or more of polyvinylpyrrolidone, hydroxypropylcellulose, microcrystalline cellulose, carboxy methylcellulose, hydroxypropylmethylcellulose, starch and starch derivatives, gelatin and gums.
Suitable diluents include one or more of lactose, starch, sugar alcohols, sucrose, microcrystalline cellulose, calcium carbonate, dicalcium phosphate and mixtures thereof.
Suitable lubricants and glidants include, but are not limited to, colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax and white beeswax.
Suitable sweetening agents may be selected from a wide range of materials such as water soluble sweetening agents, water-soluble artificial sweeteners, dipeptide based sweetening agents and mixtures thereof.
Water soluble sweetening agents encompass monosaccharides, disaccharides and polysaccharides, such as xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, maltose, corn syrup and sugar alcohols such as sorbitol, mannitol, xylitol, and mixtures thereof.
Water soluble artificial sweetening agents encompass free acid form of saccharine and its soluble salts such as sodium or calcium saccharine salts, cyclamate salts, acesulfame, aspartame and mixtures thereof.
The flavoring agents of the present invention may be selected from any FDA approved flavors for oral use.
Suitable flavoring agents include synthetic and natural flavors such as spearmint, peppermint, lemon, orange, grape, lime, grapefruit, apple, cherry, pineapple, cocoa and chocolate.
The core is surrounded by an inner coat comprising natural pigments and a water soluble polymer, which is further coated with an outer coat of a water soluble polymer.

The natural colour may be selected from dry edible, natural color pigments that at the present time do not require certification by the Food and Drug Administration since they utilize natural ingredients. Examples of these include beetroot red, carmine red, paprika orange/red, anthocyanins red/purple, annatto yellow/orange, curcumin yellow, chlorophyll green etc.
The water-soluble polymers may be selected from one or more of polyvinylpyrrolidone (PVP), gelatin, polyvinyl alcohol, starch and derivatives thereof, cellulose derivatives, such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, acrylic acid polymers, polymethacrylates, or any other pharmaceutically acceptable polymer. Particularly the polymer is hydroxypropylmethyl cellulose.
The aforementioned water soluble polymers can be applied to solid dosage form by any appropriate means, including techniques such as solution coating, spraying, dipping and brushing, in order to give integral, cohesive films which are water soluble, and thus will provide protection of the solid dosage form from attrition during transport and handling, by providing increased cohesion and mechanical strength as well as contributing to protection from deterioration caused by moisture pick-up.
The level of the coating in the inner layer containing a natural colour and a water soluble polymer is particularly between about 1% to about 5% by weight of the uncoated dosage form, more particularly about 3% to about 4.5%, by weight of the uncoated dosage form. To apply a heavier coating to solid dosage forms would not be economical, and it might adversely affect disintegration of the solid dosage forms or other properties. Too light a coating would not provide optimal properties normally expected from a coating, for example, improved friability or adequate taste masking. The level of coating in the outer layer comprising a water soluble polymer is particularly between about 0.5% to about 1.5% by weight of the uncoated dosage form. This level of coating will provide an elegant, serviceable coating to a wide variety of dosage forms.
Any commercial coating equipment may be used to apply the coating. It is important that the inlet and outlet temperatures be controlled so that they are high enough to

efficiently dry the coating to prevent the tumbling action of the already-coated solid dosage forms from damaging the newly-applied coating before more coating is applied to the same solid dosage forms.
In addition, various pharmaceutically acceptable excipients may be employed which are compatible or can be made compatible with the coating composition.
Examples include plasticizers, diluents, lubricants, glidants, sweetening agents and flavoring agents. These excipients may be present in the inner coat, outer coat or both.
Suitable plasticizers include glycerin, propylene glycol, low molecular weight polyethylene glycols, triacetin, sorbitol, acetylated monoglycerides, citrate esters, phthalate esters, mineral oil and vegetable oils.
As employed herein, the term "solid dosage form" includes without limitation, tablet, particle, micronized particle, particulate, pellet, pill, core, powder, granule, granulate, small mass, seed, specks, spheres, crystals, beads, agglomerates and mixtures thereof.
The coated solid dosage forms have the added advantage that logos and brand names can be punched onto the tablet core, and these intagliations are clearly visible following coating.
Further, the invention has an advantage not heretofore achieved with natural pigments in that FD&C and D&C lakes can be closely simulated.
The following example illustrates various aspects of the present invention. This example is for illustration only and should not be construed as limiting the scope of the invention.

Example
Core [Multivitamin tablet (Revital)]

Ingredients Blend A Percent (%) w/w
Vitamin A Acetate IP (5 lakh IU = 1gm) 0.5
Vitamin B1 IP 0.1
Vitamin B2 IP 0.15
Vitamin B6 IP 0.09
StabVit. B12(0.1%)eqto W.B12 0.15
Vitamin E Cone. BP (50 %) eq to Vit E 1.8
FolicAcid IP 0.01
Cal. Pantothenate IP 0.5
Biotin USP 0.002
Nicotinamide IP 1.6
Ginseng root extract (212.5 eq to 42.5) 2.8
Colloidal SiO2 IP eq to Si (Aerosil-200) 0.15
MCCIP(Avicel-101) 7.4
Crosscarmellose Sodium USNF (Acdisol) 0.5
Magnesium Stearate IP 0.3
Blend B
Zinc Oxide IP eq to Zn** 1.25
Potassium Iodide IP eq to I** 0.01
Carbonyl Iron eq to Fe* 2
Light Magnesium Oxide IP eq to Mg** 11.05
Maganese Sulphate USP (monohyd) eq to Mn** 0.5
Cupric Oxide eq to Cu* 0.16
Calcium carbonate eq to Ca* 14.6
Dibasic Cal Phosphate IP (anhydrous) eq to P* 36.6
Potassium Chloride eq to K* 5.08
Chromic Chloride USP (hexahyd.) eq to Cr* 0.009
Sodium Molybdate (dihydrate) eq to Mo* 0.005
Sodium Selenate (decahydrate) eq to Se* 0.008

Nickel Sulpahte (heptahydrate) eq to Ni* 0.001
Sodium Meta Vandate eq to Va* 0.001
Sodium Borate eq to B* 0.173
Stannous Chloride eq to Sn* 0.001
MCC(Avicel-101) 2.75
Croscarmellose Sodium (Acdisol) 0.9
Polyvinyl pyrrolidone IP (PVP K 30) 1.3
Purified water IP q.s
Blend C
Vitamin C Coated 3.8
Vitamin D3 Stabilised (100 IU = 1 mg) 0.3
Collodial SiO2 eq to Si IP (Aerosil-200) 0.15
MCCIP(Avicel-101) 1.5
Croscarmellose Sodium USNF (Acdisol) 0.9
Magnesium Stearate IP 0.9
Coating composition:

INGREDIENTS Percent (%)w/w (total weight of the dosage form)
Inner Coat
Hydroxypropyl methyl cellulose 2
Natural pigment 1
Glycerine 0.5
Isopropyl alcohol q.s
Purified water q.s
Outer coat
Hydroxypropyl methyl cellulose 1
Purified water q.s
Process:
1. Blends A, B & C were mixed and punched to prepare the core tablets.
2. The core tablets were pre-heated in the coating pan.
3. An aqueous dispersion of hydroxypropyl methyl cellulose and a natural pigment
was prepared.
4. The warm core tablets of step (2) were coated with the dispersion of step (3) to a
weight gain of 1-5 % w/w.

5. The coated tablets of step (4) were re-coated with hydroxypropyl methyl
cellulose to a weight gain of 0.5 to 1.5 % w/w.
6. The coated tablets of step (5) were dried.

WE CLAIM:
1. A solid dosage form comprising:
a) a core comprising one or more therapeutically active agents,
b) an inner coat surrounding said core, comprising at least one water soluble
polymer and at least one natural pigment,
c) an outer coat surrounding the inner coat comprising at least one water
soluble polymer,
wherein the outer coat constitutes from about 0.5% to about 1.5% of the total weight of the dosage form.
2. The dosage form of claim 1 wherein the core further comprises pharmaceutically
acceptable excipients selected from one or more of binders, diluents, lubricants,
glidants, sweetening agents and flavoring agents.
3. The dosage form of claim 1 wherein the water soluble polymer is selected from
one or more of starch, gums, alginates, polyvinylprrolidone, polyethylene glycol,
acrylic acid derivatives, cellulose derivatives or mixtures thereof.
4. The dosage form of claim 2 wherein the binder is selected from one or more of
polyvinylpyrrolidone, hydroxypropylcellulose, microcrystalline cellulose, carboxy
methylcellulose, hydroxypropylmethylcellulose, starch and starch derivatives,
gelatin and gums.
5. The dosage form of claim 2 wherein the diluent is selected from lactose, starch,
sugar alcohols, sucrose, calcium carbonate, dicalcium phosphate and mixtures
thereof.
6. The dosage form of claim 2 wherein the lubricant and glidant are selected from
colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate,
talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax,
yellow beeswax and white beeswax.

7. The dosage form of claim 1 wherein the inner and outer coat further comprise
pharmaceutically acceptable excipients selected from one or more of
plasticizers, diluents, lubricants, glidants, sweetening agents and flavoring
agents.
8. The dosage form of claim 7 wherein the plasticizer is selected from glycerin,
propylene glycol, low molecular weight polyethylene glycols, triacetin, sorbitol,
acetylated monoglycerides, citrate esters, phthalate esters, mineral oil and
vegetable oils.
9. A process for coating a solid dosage form of claim 1 comprising the steps of:

a) preparing an aqueous solution of at least one water soluble polymer and
at least one natural pigment,
b) coating the aqueous solution of step (a) over the active core of the solid
dosage form to provide the inner coat, and
c) coating the inner coat of step (b) with at least one water soluble polymer
to form an outer coat,
wherein the outer coat constitutes from about 0.5% to about 1.5% of the total weight of the dosage form.
10. A solid dosage form and process of coating thereof substantially as described
herein.